7tva | pdb_00007tva
Stat5a Core in complex with AK2292
Structural highlights
FunctionSTA5A_HUMAN Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Mediates cellular responses to ERBB4. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the GAS element and activates PRL-induced transcription. Regulates the expression of milk proteins during lactation.[1] Publication Abstract from PubMedSignal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target, but successful targeting of STAT5 has proved to be difficult. Here we report the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. AK-2292 induces degradation of STAT5A/B proteins with an outstanding selectivity over all other STAT proteins and more than 6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human chronic myeloid leukemia (CML) xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose schedules. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and the therapeutic potential of selective STAT5 protein depletion and inhibition but also a promising lead compound toward ultimate development of a STAT5-targeted therapy. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo.,Kaneshige A, Bai L, Wang M, McEachern D, Meagher JL, Xu R, Wang Y, Jiang W, Metwally H, Kirchhoff PD, Zhao L, Jiang H, Wang M, Wen B, Sun D, Stuckey JA, Wang S Nat Chem Biol. 2023 Feb 2. doi: 10.1038/s41589-022-01248-4. PMID:36732620[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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